CN101481720A - Method for enzyme-catalyzed synthesis of 5-aza cytidine ester derivative in mixed solvent - Google Patents
Method for enzyme-catalyzed synthesis of 5-aza cytidine ester derivative in mixed solvent Download PDFInfo
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- CN101481720A CN101481720A CNA2009100369053A CN200910036905A CN101481720A CN 101481720 A CN101481720 A CN 101481720A CN A2009100369053 A CNA2009100369053 A CN A2009100369053A CN 200910036905 A CN200910036905 A CN 200910036905A CN 101481720 A CN101481720 A CN 101481720A
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Abstract
The invention relates to a synthetic method of enzymatic 5-azacytidine ester derivative in mixed solvent. 5-azacytidine and acyl donor are added in a mixed solvent system. The mol ratio of the acyl donor to the 5-azacytidine is 1.1-30 to 1. Enzyme is added according to the mass ratio of 0.1-10 to 1 of the 5-azacytidine to the enzyme. The acylation reaction is carried out with the temperature of 20-70 DEG C and the oscillation speed of 100-300rpm under the normal pressure. After the separation, the 5-azacytidine ester derivative is obtained. The synthetic method has the advantages of moderate reaction conditions, environment-friendly property, high region selectivity for the reaction, simple and controllable reaction process, easily separated products, etc.
Description
Technical field
The present invention relates to method at the synthetic compound shown in general formula (I) of enzyme catalysis in the mixed solvent.
Background technology
5-azacytidine (5-azacytidine) is a class non-natural nucleoside, be clinically a kind of important treatment leukemia medicament (Momparler R.L., et al, Leuk.Res., 1984,8:1043-1049).In on May 19th, 2004 by FDA approval listing, applying for the registration of number is NDA050794, is used for the treatment of osteomyelodysplasia syndromes (Myelodysplastic Syndrome, prescription drugs MDS).Studies show that this drug main will make the DNA of abnormal blood cell in the marrow hypomethylation take place and produce anti-leukocythemia liveness by disturbing the process that methylates of DNA.Its antileukemie mechanism is: after carrying out phosphorylation under the effect of deoxycytidine kinase, become the activity inhibitor of dna methylation enzyme (DNA-(cytosine(Cyt)-5) methyltransgerase), thereby induced the cancer cells differentiation or activated tumor suppressor gene, show anti-tumor activity (Cheng X., Curr.Opin.Struct.Biol., 1995,5:4-10).
But 5-azacytidine still exists many shortcomings (Beisler A.J., J.Med.Chem., 1978,21:204-208 in clinical application at present; Laliberte J., et al, Cancer Chemother.Pharmacol., 1992,30:7-11; Chabot G.G., et al, Biochem.Pharmacol., 1983,32:1327-1328): the insertion of 5 nitrogen-atoms causes the pyrimidine ring instability in (1) cytosine(Cyt), is subjected to the attack of nucleophilic reagent easily, so this medicine is very unstable in the aqueous solution, need interim preparation to carry out administration clinically; (2) under the effect of blood plasma cytidine deaminase, 5-azacytidine can be degraded to nonactive metabolite uridine rapidly, causes the transformation period in human plasma too short; (3) because the disappearance of deoxycytidine kinase or be subjected to the feedback inhibition of excessive dCTP and can not carry out phosphorylation by the catalysis 5-azacytidine in the body can not become the activity inhibitor of dna methylation enzyme, thus can not the inducing cancer cell differentiation, bring into play its anti-tumor activity.
Nucleoside medicine is water-soluble strong, fat-soluble low, is difficult to permeate through cell membranes, so oral administration biaavailability is lower.Studies show that in a large number; the glycosyl of former medicine is carried out suitable acidylate transformation and the nucleosides ester kind new medicine that obtains not only shows higher oral administration biaavailability; and have an antiviral or anti-tumor activity higher than former medicine; wider anticancer and antiviral spectrum; strengthened its stability in blood plasma, prolonged action time (DeClercq, E.and Field H.J.; Br.J.Pharmacol., 2006.147 (1): 1-11).
It is numerous that nucleoside compound sugar ring is gone up hydroxyl, and reactive behavior is similar.When adopting general chemical process direct esterification, regioselectivity is low, easily produces a large amount of by products, the product separation difficulty; Be the acylate of synthetic specific position, need encircle hydroxyl to sugar and protect and go operation such as protection, many, the complex process of reactions steps; Simultaneously, this method adopts basic catalyst usually, easily produces alkali waste, to environment cause severe contamination (Xia Z.P., Wiebe L.I., Miller G.G., et al.Arch.Pharm., 1999,332:286-294).And the enzyme process mild condition, the height of efficient catalytic acylation reaction, and regioselectivity at normal temperatures can synthesize the ester derivative of ad hoc structure as required, and technology is simple, environmental friendliness.
Summary of the invention
The objective of the invention is to problem, propose the method for the synthetic 5-azacytidine ester of enzyme catalysis of a kind of product purity height, technology simple controllable at the prior art existence.
The present invention is an acry radical donor with carboxylicesters or acid anhydrides, utilizes the enzyme catalysis 5-azacytidine to carry out acylation reaction, synthetic compound shown in general formula (I).By select different enzymes can synthesize 3 of 5-azacytidine '-ester, 5 '-ester and 3 ', 5 '-diester deriv.Purpose of the present invention is achieved through the following technical solutions:
The method of the synthetic 5-azacytidine ester derivative of enzymatic in a kind of mixed solvent: in mixed solvent system, add 5-azacytidine and acry radical donor; the mol ratio of acry radical donor and 5-azacytidine is 1.1-30:1; mass ratio by 5-azacytidine and enzyme is that 0.1-10:1 adds enzyme; in temperature is that 20-70 ℃, hunting speed are to carry out acylation reaction under 100-300rpm, the normal pressure, separates that to obtain 5-azacytidine ester derivative general formula as follows:
R wherein
1And R
2Represent carboxyl groups or hydrogen atom, but R
1And R
2Be not hydrogen atom simultaneously
Described enzyme is to derive from lipase, the proteolytic enzyme one or more; Described lipase derives from antarctic candida (Candida antarctica), the thermophilic hyphomycete of cotton shape (Thermomyces lanuginosus), rice black root Mucor (Rhizomucor miehe), pseudomonas cepacia (Burkholderia cepacia), pseudomonas fluorescens (Pseudomonas fluorescens), aspergillus niger (Aspergillus niger), rice black wool mould (Mucor miehei) or Pancreas Sus domestica; Described proteolytic enzyme derives from honey aspergillus (Aspergillusmelleus), subtilis (Bacillus subilis) or Bacillus licheniformis (Bacilluslicheniformis);
Described acry radical donor is carboxylicesters or acid anhydrides; Described mixed solvent system is the mixed system of the mixed system of organic solvent or organic solvent and ionic liquid; The mixed system of described organic solvent is that two kinds in the aprotic organic solvent are that 1-19:1 mixing gets according to volume ratio; The mixed system of described organic solvent and ionic liquid is the mixture that contains low anionic ionic liquid of nucleophilicity and aprotic organic solvent; Ionic liquid volume content in the mixed system of organic solvent and ionic liquid is 2-95%.
For further realizing the object of the invention, described carboxylicesters is preferably fatty acid ester, and described fatty acid ester is carbon chain lengths C2-C24, contains the fatty acid ester of 0-6 two keys.
Described carboxylicesters is preferably aromatic ester, and described aromatic ester is preferably the aromatic ester that contains 1 above phenyl ring.Described acid anhydrides is preferably the fatty acid anhydride of carbon chain lengths C2-C18.
Described aprotic organic solvent is preferably dimethyl sulfoxide (DMSO), N, dinethylformamide, pyridine, acetonitrile, acetone, tetrahydrofuran (THF), diox, ethyl acetate, isopropyl ether, normal hexane or hexanaphthene.
The negatively charged ion of described ionic liquid is preferably tetrafluoroborate ion, hexafluorophosphoricacid acid ions, two (trifluoromethyl sulphonyl) imines ion or amino acid ion.
Described hunting speed is preferably 150-250rpm; Described temperature of reaction is preferably 40-60 ℃.
Described being separated into after esterification finishes, filter dezymotize, vacuum concentration, use methyl alcohol, ethanol or ethyl acetate crystallization again, perhaps pass through silica gel column chromatography separating purification.
The present invention has following advantage compared with prior art:
(1) adopting biological catalyst efficiently---the ester derivative of enzyme catalysis 5-azacytidine is synthetic.Enzymatic reaction has high selectivity, and by select different zymins can synthesize 3 of 5-azacytidine '-ester, 5 '-ester and 3 ', 5 '-diester deriv, therefore overcome traditional chemical method selectivity low, easily generate by product, need protection and shortcoming such as deprotection operation and productive rate be low;
(2) the present invention need not radical protection and deprotection operation, and reaction process is simple and easy to control, and product is easily separated;
(3) the present invention is to be that 20-70 ℃, hunting speed are under 100-300rpm, the condition of normal pressure in temperature, utilizes enzyme catalysis to prepare the ester derivative of 5-azacytidine, reaction conditions gentleness, environmental friendliness.
Embodiment
For better understanding the present invention, the present invention is described in further detail below in conjunction with embodiment, but the scope of protection of present invention is not limited to the scope that embodiment represents.
5 of embodiment 1:5-azacytidine '-acetic ester synthetic
With 5-azacytidine (100mg, 0.41mmol), diacetyl oxide (6.15mmol), 40mL normal hexane/pyridine (1/3, v/v) add in the sealing tool plug triangular flask, then add 500mg and derive from the immobilized lipase B of Candidaantarctica, place vibration in 30 ℃, the constant temperature oscillator of 200rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 106mg, yield is 90%, white powder, purity is greater than 99%.
3 ', 5 of embodiment 2:5-azacytidine '-diacetate esters synthetic
With 5-azacytidine (100mg, 0.41mmol), vinyl-acetic ester (12.3mmol), 40mL normal hexane/pyridine (1/3, v/v) add in the sealing tool plug triangular flask, then add 200mg and derive from the immobilized lipase of Thermomyces lanuginosu and the immobilized lipase that 400mg derives from Burkholderia cepacia, place vibration in 40 ℃, the constant temperature oscillator of 200rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 121mg, yield is 90%, white powder, purity is greater than 99%.
5 of embodiment 3:5-azacytidine '-butyric ester synthetic
With 5-azacytidine (100mg, 0.41mmol), vinyl butyrate (6.15mmol), 40mL isopropyl ether/pyridine (2/7, v/v) add in the sealing tool plug triangular flask, then add 500mg and derive from the immobilized lipase B of Candidaantarctica, place vibration in 45 ℃, the constant temperature oscillator of 250rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 115mg, yield is 89%, white powder, purity is greater than 99%.
3 of embodiment 4:5-azacytidine '-butyric ester synthetic
With 5-azacytidine (100mg, 0.41mmol), vinyl butyrate (4.1mmol), 40mL normal hexane/pyridine (2/3, v/v) add in the sealing tool plug triangular flask, then add 400mg and derive from the immobilized lipase of Burkholderia cepacia, place vibration in 40 ℃, the constant temperature oscillator of 200rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 103mg, yield is 80%, white powder, purity is greater than 99%.
5 of embodiment 5:5-azacytidine '-octanoate synthetic
With 5-azacytidine (100mg, 0.41mmol), sad vinyl acetate (6.15mmol), 40mL normal hexane/pyridine (1/3, v/v) add in the sealing tool plug triangular flask, then add 500mg and derive from the immobilized lipase B of Candidaantarctica, place vibration in 40 ℃, the constant temperature oscillator of 150rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 140mg, yield is 92%, white powder, purity is greater than 99%.
5 of embodiment 6:5-azacytidine '-octanoate synthetic
With 5-azacytidine (100mg, 0.41mmol), sad acetoxime ester (4.10mmol), 40mL[C
4MIm] PF
6/ pyridine (1/6, v/v) add in the sealing tool plug triangular flask, then add the immobilized lipase B that 500mg derives from Candida antarctica, place vibration in 60 ℃, the constant temperature oscillator of 250rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 145mg, yield is 95%, white powder, purity is greater than 99%.
5 of embodiment 7:5-azacytidine '-laurate synthetic
With 5-azacytidine (100mg, 0.41mmol), vinyl laurate (6.15mmol), 40mL normal hexane/pyridine (1/3, v/v) add in the sealing tool plug triangular flask, then add 600mg and derive from the immobilized lipase of Thermomyces lanuginosus, place vibration in 40 ℃, the constant temperature oscillator of 200rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 148mg, yield is 85%, white powder, purity is greater than 99%.
5 of embodiment 8:5-azacytidine '-laurate synthetic
With 5-azacytidine (100mg, 0.41mmol), vinyl laurate (6.15mmol), 40mL[C
4MIm] BF
4/ pyridine (1/4, v/v) add in the sealing tool plug triangular flask, then add the 100mg subtilisin, place vibration in 50 ℃, the constant temperature oscillator of 250rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 157mg, yield is 90%, white powder, purity is greater than 99%.
5 of embodiment 9:5-azacytidine '-cetylate synthetic
With 5-azacytidine (100mg, 0.41mmol), palmitinic acid vinyl acetate (6.15mmol), 40mL normal hexane/pyridine (1/3, v/v) add in the sealing tool plug triangular flask, then add 500mg and derive from the immobilized lipase of Burkholderia cepacia, place vibration in 40 ℃, the constant temperature oscillator of 200rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 148mg, yield is 75%, white powder, purity is greater than 99%.
5 of embodiment 10:5-azacytidine '-stearate synthetic
With 5-azacytidine (100mg, 0.41mmol), stearic acid vinyl ester (6.15mmol), 40mL normal hexane/pyridine (1/3, v/v) add in the sealing tool plug triangular flask, then add 500mg and derive from the immobilized lipase B of Candidaantarctica, place vibration in 40 ℃, the constant temperature oscillator of 200rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 176mg, yield is 84%, white powder, purity is greater than 99%.
5 of embodiment 11:5-azacytidine '-benzoic ether synthetic
With 5-azacytidine (100mg, 0.41mmol), vinyl benzoate (2.05mmol), 40mL normal hexane/pyridine (1/3, v/v) add in the sealing tool plug triangular flask, then add 500mg and derive from the immobilized lipase B of Candidaantarctica, place vibration in 70 ℃, the constant temperature oscillator of 250rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 127mg, yield is 89%, white powder, purity is greater than 99%.
From the foregoing description as can be seen; this research under the reaction conditions of gentleness (30-70 ℃; 150-250rpm); and the effect of green biological catalyst (immobilized enzyme preparation) down; without loaded down with trivial details protection/deprotection steps consuming time; the various ester derivatives that promptly efficiently synthesized 5-azacytidine by single step reaction; after the reaction; can remove immobilized enzyme by filtering; follow-up product separation and purification operation is simple; easy to operate; yield reaches 70-92% behind the purifying, and it is low to have overcome traditional chemical method selectivity; easily generate by product; shortcoming such as need protection and deprotection operation and productive rate be low.
Claims (8)
1, the method for the synthetic 5-azacytidine ester derivative of enzymatic in a kind of mixed solvent; it is characterized in that: in mixed solvent system, add 5-azacytidine and acry radical donor; the mol ratio of acry radical donor and 5-azacytidine is 1.1-30:1; mass ratio by 5-azacytidine and enzyme is that 0.1-10:1 adds enzyme; in temperature is that 20-70 ℃, hunting speed are to carry out acylation reaction under 100-300rpm, the normal pressure, separates that to obtain 5-azacytidine ester derivative general formula as follows:
R wherein
1And R
2Represent carboxyl groups or hydrogen atom, R
1And R
2Be not hydrogen atom simultaneously
Described enzyme is to derive from lipase, the proteolytic enzyme one or more; Described lipase derives from antarctic candida, the thermophilic hyphomycete of cotton shape, rice black root Mucor, pseudomonas cepacia, pseudomonas fluorescens, aspergillus niger, the mould or Pancreas Sus domestica of rice black wool; Described proteolytic enzyme derives from honey aspergillus, subtilis or Bacillus licheniformis;
Described acry radical donor is carboxylicesters or acid anhydrides;
Described mixed solvent system is the mixed system of the mixed system of organic solvent or organic solvent and ionic liquid; The mixed system of described organic solvent is that two kinds in the aprotic organic solvent are that 1-19:1 mixing gets according to volume ratio; The mixed system of described organic solvent and ionic liquid is the mixture that contains low anionic ionic liquid of nucleophilicity and aprotic organic solvent; Ionic liquid volume content in the mixed system of organic solvent and ionic liquid is 2-95%.
2, method according to claim 1 is characterized in that described carboxylicesters is a fatty acid ester, and described fatty acid ester is carbon chain lengths C2-C24, contains the fatty acid ester of 0-6 two keys.
3, method according to claim 1 is characterized in that described carboxylicesters is an aromatic ester, and described aromatic ester is the aromatic ester that contains 1 above phenyl ring.
4, method according to claim 1 is characterized in that described acid anhydrides is the fatty acid anhydride of carbon chain lengths C2-C18.
5, method according to claim 1 is characterized in that aprotic organic solvent is dimethyl sulfoxide (DMSO), N, dinethylformamide, pyridine, acetonitrile, acetone, tetrahydrofuran (THF), diox, ethyl acetate, isopropyl ether, normal hexane or hexanaphthene.
6, method according to claim 1, the negatively charged ion that it is characterized in that described ionic liquid are tetrafluoroborate ion, hexafluorophosphoricacid acid ions, two (trifluoromethyl sulphonyl) imines ion or amino acid ion.
7, method according to claim 1 is characterized in that in hunting speed be 150-250rpm; Described temperature of reaction is 40-60 ℃.
8, method according to claim 1 is characterized in that: described being separated into after esterification finishes, filter dezymotize, vacuum concentration, use methyl alcohol, ethanol or ethyl acetate crystallization again, perhaps pass through silica gel column chromatography separating purification.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102851337A (en) * | 2012-08-31 | 2013-01-02 | 华南理工大学 | Method for realizing protective reaction for hydroxyl groups of cytidine compound through catalysis of Aspergillus oryzae cells |
| CN108290920A (en) * | 2015-11-27 | 2018-07-17 | 大原药品工业株式会社 | 5 '-dibenzyl phosphates of 5-azacitidine or 2＆apos |
-
2009
- 2009-01-22 CN CNA2009100369053A patent/CN101481720A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102851337A (en) * | 2012-08-31 | 2013-01-02 | 华南理工大学 | Method for realizing protective reaction for hydroxyl groups of cytidine compound through catalysis of Aspergillus oryzae cells |
| CN102851337B (en) * | 2012-08-31 | 2014-04-02 | 华南理工大学 | Method for realizing protective reaction for hydroxyl groups of cytidine compound through catalysis of Aspergillus oryzae cells |
| CN108290920A (en) * | 2015-11-27 | 2018-07-17 | 大原药品工业株式会社 | 5 '-dibenzyl phosphates of 5-azacitidine or 2＆apos |
| CN108290920B (en) * | 2015-11-27 | 2021-08-10 | 大原药品工业株式会社 | 5 '-dibenzyl phosphate of 5-azacytidine or 2' -deoxy-5-azacytidine |
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Application publication date: 20090715 |